tbuckley/cabot-search huggingface dataset:
Abstract SY31-02: Determinants of hypoxia in pancreatic cancer and identification of ULK1 as a potential therapeutic target
Authors: Ji Zhang, Dan Cojocari, Rob Cairns, Marianne Koritzinsky, Bradly G. Wouters
Journal: Cancer Research (2023)

Abstract The effectiveness of radiation treatment is impacted by spatially defined features of the tumor microenvironment including areas of tumor hypoxia. This is due in part to direct protection against radiation damage by hypoxia, as well as through the influence of hypoxia on tumor, stroma and immune cell phenotypes. Despite this understanding, our progress in advancing therapies to address tumor hypoxia in patients have been largely unsuccessful. This is driven in part to the incredible variability in tumor hypoxia across patients as well as to a limited understanding of the underlying causes and consequences of hypoxia on an individual patient basis. As a step towards more precision approaches for hypoxia directed therapies we are characterizing hypoxia and its causes in individual patients and in matched patient derived xenografts. Our data reveal a striking variation in hypoxia across patients, and a corresponding variation in both oxygen consumption and hypoxia tolerance in patient derived organoids. We hypothesize that levels of hypoxia within individual tumors are determined through separate processes that drive changes in oxygen demand coupled with those that influence adaptation and survival to hypoxic stress. We have also identified ULK1 as a key contributor to both of these processes. Loss or inhibition of ULK1, a gene activated downstream of the unfolded protein response during hypoxia, results in defects in both mitochondrial and ER turnover leading to increases in both oxygen consumption and ER stress. Consequently, knockdown of ULK1 in established pancreatic cancer xenografts results in development of more hypoxia, while at the same time promotes the death of cells that become hypoxic. This has a dramatic impact on tumor growth, leading to complete remission in some models and suggesting that ULK1 should be pursued as a tumor microenvironment therapeutic target. Citation Format: Ji Zhang, Dan Cojocari, Rob Cairns, Marianne Koritzinsky, Bradly G. Wouters. Determinants of hypoxia in pancreatic cancer and identification of ULK1 as a potential therapeutic target. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr SY31-02.
Abstract 2619: Characterization of RAS assembly architectures in living cells
Authors: Zhiwei Zhou, Xing-Xiao Li, Cynthia Meyer, Yu-An Zhang, Deekshi Angira, Kenneth Westover
Journal: Cancer Research (2023)

Abstract Assembly of RAS proteins and RAS effectors into “nanoclusters” at the cell membrane regulates RAS signaling output. The structure and composition of membrane-bound RAS complexes is dynamic, but defined states appear to exist. We previously found biological and biophysical evidence for two different models of membrane-bound RAS assemblies where RAS proteins form symmetric or asymmetric RAS-RAS interactions. It is unknown what functions these two architectures might serve and what determinants these nanoclusters might be subject to. To further characterize which architectural states occur in various biological scenarios, we developed a plate-based assay to detect RAS-RAS interactions in cells. The system controls for RAS expression and can be used to discriminate symmetric and asymmetric RAS-RAS interactions. It can also be used to assess the relative contributions of the G domain (1-166) and hypervariable region (HVR) in mediating RAS-RAS interactions. We found that RAS isoforms can homo- and hetero-dimerize and observed that the G domain contributes to RAS-RAS interactions, but that the HVR does not. We also found that the primary determinant of HVR interaction with the membrane is electrostatic charge. Regarding cancer-causing mutations, we found that in the KRAS G12D context, RAS-RAS interactions appear to favor asymmetric RAS-RAS interactions while KRAS Q61H favors symmetric RAS-RAS interactions. Citation Format: Zhiwei Zhou, Xing-Xiao Li, Cynthia Meyer, Yu-An Zhang, Deekshi Angira, Kenneth Westover. Characterization of RAS assembly architectures in living cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2619.
Abstract 6204: DNA-PK inhibition augment the cancer specific cytotoxicity of mitotic MTH1 inhibitor OXC-101
Authors: Akhilesh Nagesh Danda, Helge Gad, Martin Scobie, Laura Martínez-López, Nuria Pastor Carrillo, Manuel Luis Orta, Thomas Helleday, Ulrika warpman berglund, Kumar Sanjiv
Journal: Cancer Research (2023)

Abstract DNA-dependent protein kinase (DNA-PK) plays an important role in the repair of DNA double-strand breaks via the non-homologous end joining (NHEJ) pathway. In addition to its role in the NHEJ pathway, DNA-PK is also known to have an emerging role in cell cycle progression and mitosis. Some studies have shown that depletion or inhibition of DNA-PK inhibitors leads to a delay in the transition from metaphase to anaphase. The mitotic MTH1 inhibitor OXC-101(TH1579, karonudib) is a dual inhibitor that both targets MTH1 and disrupts tubulin polymerization in cancer cells, causing DNA damage and mitotic catastrophe in cancer cells. Based on the involvement of DNA-PK in mitosis, we hypothesized that depletion/inhibition of DNA-PK might enhance the DNA damage and mitotic catastrophic effect of OXC-101.To test our hypothesis, we performed an in vitro drug combination experiment using the DNA-PK inhibitor nedisertib with OXC-101 in non-small cell lung carcinoma NSCLC (H460,A549), uveal melanoma (MP -38, MP -41 and MP46), osteosarcoma (U2OS) and) and neuroblastoma (IMR32, Kelly, SKNFI) cancer cell lines and non-cancerous foreskin fibroblasts(VH-10, BjhTERT). We found cancer-specific synergistic drug interactions between nedisertib and OXC-101. Combined treatment of nedisertib and OXC-101 to H460 and MP46 increased expression of s10H3 (mitotic marker) and the apoptosis marker (cPARP) compared with single treatment. However, there was no additional increase in expression of the DNA damage markerγH2AX with combined treatment. We also performed annexin V staining by FACS on MP38 andMP48 cells and observed a significant increase in the apoptotic population with combination treatment compared with single treatment. Imaging live cells, we observed a significant delay or arrest in the mitotic phase followed by death of cancer cells in mitosis in response to combination treatment, whereas cells treated individually with nedisertib or OXC-101 continued to proliferate and progress to the next phase of the cell cycle. These data suggest that the DNA-PK inhibitor may enhance the cytotoxic effect of OXC-101specifically in cancer cells. In addition, we will conduct an in-depth mechanistic study of how depletion/inhibition of DNA-PK enhances the cytotoxicity of OXC-101 and validate the drug combination in an appropriate preclinical mouse model. Citation Format: Akhilesh Nagesh Danda, Helge Gad, Martin Scobie, Laura Martínez-López, Nuria Pastor Carrillo, Manuel Luis Orta, Thomas Helleday, Ulrika warpman berglund, Kumar Sanjiv. DNA-PK inhibition augment the cancer specific cytotoxicity of mitotic MTH1 inhibitor OXC-101 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6204.
Abstract 3513: Developing a 3D biomimetic liver metastatic niche model for pancreatic cancer
Authors: Mahsa Pahlavanneshan, Weikun Xiao, Chae Young Eun, Chang-Il Hwang, Reginald Hill
Journal: Cancer Research (2023)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the 3rd leading cause of cancer death in the Unites States with a 5-year survival rate of only 11%. Early diagnosis is very difficult and thus 53% of patients are diagnosed after metastasis has already occurred, with the liver being the most frequently affected site. Both primary tumors and metastases have highly fibrotic stroma. Thus, stromal targeting agents have the potential to benefit patients, even those with metastatic disease. However, in addition to different resident fibroblasts, a study based on a rapid autopsy program of metastatic PDAC patients showed that tumor ECM density is actually lower at sites of liver metastasis compared to the primary tumor. These results highlight some of the differences between the microenvironment of the liver metastatic niche (LMN) compared to that of the primary tumor. Thus, to best help patients, models which recapitulate the LMN are needed. We developed a 3D biomimetic model to co-culture PDAC organoids and host matching primary CAFs to recapitulate the desmoplastic environment of primary PDAC. Our preliminary results show that primary site derived CAFs induce organoid growth, chemoresistance, and ECM remodeling when co-cultured with PDAC organoids. Utilizing paired organoids which metastasized to the liver (LM organoids), we tested if primary site derived CAFs would have the same effect on LMs. Interestingly, we observed that while LM organoids were intrinsically more drug resistant, co-culture with primary site derived CAFs had no effect on chemoresistance or ECM remodeling. Next, we utilized a metastasis associated fibroblast (MAF) liver cell line to investigate the role of MAFs in tumor growth, chemoresistance, and ECM remodeling. Our results show that primary and metastatic organoids use different mechanism to induce ECM stiffness triggered by fibroblast activation and remodeling in their resident fibroblasts. Citation Format: Mahsa Pahlavanneshan, Weikun Xiao, Chae Young Eun, Chang-Il Hwang, Reginald Hill. Developing a 3D biomimetic liver metastatic niche model for pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3513.
Abstract 5876: Sorafenib and Lenvatinib induce vascular responses in patient derived HCC on-Chip models
Authors: Orsola Mocellin, Abbie Robinson, Aleksandra Olczyk, Stephane Treillard, Thomas Olivier, Chee Ng, Jeroen Heijmans, Désiréé Goubert, Arthur Stok, Gilles van Tienderen, Monique Verstegen, Sebastian Trietsch, Henriëtte Lanz, Paul Vulto, Jos Joore, Karla S. Queiroz
Journal: Cancer Research (2023)

Abstract Hepatocellular carcinoma (HCC) is the most common type of liver cancer. Its incidence is increasing, and is closely related to advanced liver disease. Interactions in the HCC microenvironment between tumor cells and the associated stroma actively regulate tumor initiation, progression, metastasis, and therapy response. In the present study, we used the OrganoPlate graft to establish a co-culture system consisting of dissociated HCC tumors (HCC 1-8) and cell lines, HCC derived fibroblasts and vasculature. Cultures were prepared and validated by assessing their response to Sorafenib and Lenvatinib (72 hours). Cultures had their viability (alamar blue assay), and chemokine/cytokine levels in the supernatant (Luminex) determined. In addition, the organization of the vasculature in the tumor compartment was studied through immunostainings, confocal imaging, and subsequent morphological analyses. HCC models were characterized by a range of specific markers, tumor (albumin), endothelial (CD31 and VE-Cadherin) and stromal (aSMA) cells. CD31 immunostained cultures were imaged, and morphology changes quantified. Sorafenib and Lenvatinib induced changes in the tumor vasculature area and organization. Hereby, we present vascularized patient-derived HCC models that include relevant cellular players of the HCC microenvironment. These co-cultures are highly suitable for studying specific cell types as well as patient-specific responses. We envision that this patient derived model will evolve to become a platform for understanding the interplay between angiogenesis, stroma and immune infiltrate in HCC. Citation Format: Orsola Mocellin, Abbie Robinson, Aleksandra Olczyk, Stephane Treillard, Thomas Olivier, Chee Ng, Jeroen Heijmans, Désiréé Goubert, Arthur Stok, Gilles van Tienderen, Monique Verstegen, Sebastian Trietsch, Henriëtte Lanz, Paul Vulto, Jos Joore, Karla S. Queiroz. Sorafenib and Lenvatinib induce vascular responses in patient derived HCC on-Chip models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5876.
Abstract 3728: A novel, simplified, streamlined workflow for high-throughput whole transcriptome RNA-seq library preparation for a variety of sample types
Authors: Chelsea Pinegar, Dora Posfai, Gautam Naishadham, Bradley W. Langhorst, Keerthana Krishnan
Journal: Cancer Research (2023)

Abstract RNA sequencing (RNA-seq) has become an invaluable tool in the study of biology, but often requires multiple days to process samples from total RNA to final libraries that can be loaded on to a sequencer. Researchers use RNA-seq to gain insight into whole tumor gene expression, and in combination with other omics data make treatment decisions. In cancer research, time taken to yield sequencing results can be critical for clinical samples. Within oncology research, libraries are often prepared from RNA sourced from formalin-fixed, paraffin-embedded (FFPE) tissues which can be particularly challenging and is not compatible with all library preparation methods. Here, we present a new protocol that allows users to easily generate robust RNA-seq libraries from a variety of sample types in a single day from 25-250 ng of total RNA. Compatible with poly(A) enrichment or ribosomal RNA depletion, this new workflow has reduced preparation time by about 40% compared to current library prep kits without sacrificing quality of libraries or any sequencing metrics, including 5’-3’ coverage, GC bias. Our new method provides equivalent transcript expression in FFPE samples when compared with existing protocols. In addition to master mixed components and reduced incubation times, the reduction in bead cleanup steps significantly reduces hands-on time for library preparation, simplifying and streamlining the process. This new library preparation method is also ideal for processing samples of various inputs with a single condition at every step throughout the protocol, without modifying cycling conditions or dilutions based on input amount. This workflow provides a great advantage in efficiently generating RNA-seq libraries while simultaneously maintaining high quality sequencing results and compatibility with both high- and low-quality RNA such as FFPE. Citation Format: Chelsea Pinegar, Dora Posfai, Gautam Naishadham, Bradley W. Langhorst, Keerthana Krishnan. A novel, simplified, streamlined workflow for high-throughput whole transcriptome RNA-seq library preparation for a variety of sample types. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3728.
Abstract 444: Inhibition of GPR68 signaling activated downstream of the Warburg effect induces cell death and enhances radiosensitivity in diverse cancer cell types
Authors: Leif R. Neitzel, Han G. Lee, Hem Shukla, Javed Mahmood, Charles H. Williams, Charles C. Hong
Journal: Cancer Research (2023)

Abstract Introduction: The Warburg effect, a phenomenon in which cancer cells produce energy via aerobic glycolysis, is a hallmark of cancer. A key physiological consequence of the Warburg effect is lactate secretion, which acidifies the tumor milieu, thought to confer tumor resistance to chemotherapy and radiotherapy. Yet, the molecular mechanism of this resistance is not well understood. Ogremorphin, a small molecule inhibitor of an extracellular pH sensing receptor, GPR68, was found to inhibit the growth and survival of Glioblastomas. However, the consequences of GPR68 inhibition on carcinomas alone and in combination with radiation are unclear. The aim of this study was to investigate the effect of ogremorphin alone and in combination with radiation on multiple cancer cell lines. Methods: 1) siRNA and CRISPR-interference knockdown of GPR68 in two carcinoma cell lines Panc02 (pancreatic ductal adenocarcinoma) and A549 (lung cell carcinoma). 2) Treatment of pancreatic and lung carcinomas with GPR68 inhibitor ogremorphin alone and with ionizing radiation. 3) Cell viability (MTT), clonogenic assays, and cell cycle analysis via flow cytometry were performed. 4) Lipid peroxidation study for induction of ferroptosis. The interaction between ogremorphin and radiation was evaluated using the combination index. Results: Knockdown of GPR68 had significant effects on cell survival. Exposures of ogremorphin in clonogenic assays indicated a significant effect in reducing colony size, but not on the number of colonies, in both carcinoma cell lines. Moreover, ogremorphin significantly increased the efficacy of irradiation on the reduction of colony size. Although ogremorphin had no effect on cell cycle alone, it had a synergistic increase in G2 phase cells with radiation. Finally, GPR68 inhibition indicated synergistic activity with radiation for the induction of ferroptosis. Conclusion. GPR68 inhibition induces ferroptosis in cancer cells on its own, but also synergistically with ionizing radiation. This study suggests that GPR68 is a key cancer survival pathway activated by the acidic tumor milieu/Warburg effect, and that the ogremorphin class of molecules may be suitable candidates for combination therapy in lung and pancreatic carcinoma. Citation Format: Leif R. Neitzel, Han G. Lee, Hem Shukla, Javed Mahmood, Charles H. Williams, Charles C. Hong. Inhibition of GPR68 signaling activated downstream of the Warburg effect induces cell death and enhances radiosensitivity in diverse cancer cell types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 444.
Effectiveness of Psychotherapy on Prevention of Suicidal Re-Attempts in Psychiatric Emergencies: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials
Authors: Hyunsuk Jeong, Hyeon Woo Yim, Seung-Yup Lee, Marc N. Potenza, Na-Jin Kim
Journal: Psychotherapy and Psychosomatics (2023)

Introduction: Many psychological interventions aim to prevent suicide, but there is limited information regarding their comparative effectiveness. Objectives: We conducted a systematic review and network meta-analysis to evaluate the relative effects of psychological interventions for preventing suicide re-attempts in psychiatric emergencies. Methods: We searched PubMed, Embase, Cochrane, and PsycINFO from inception to December 1, 2022. Selection and data extraction were conducted independently by two reviewers based on prespecified criteria. We evaluated the efficacy of interventions, potential effect moderators, and study quality both within individual studies and across studies. Global and local inconsistencies and publication bias were explored. The primary outcome was suicide re-attempt rate. The network meta-analysis was conducted using the “netmeta” package in R. The protocol was registered with PROSPERO (CRD42021291407). Results: There were 3,155 participants from 26 randomized controlled trials included in the network meta-analysis. Cognitive behavioral therapy (CBT) was the only intervention that was more effective than a common comparator for reducing suicide re-attempts among psychological interventions in both direct and indirect comparisons (odds ratio: [95% confidence interval], 0.46 [0.25–0.85] vs. 0.47 [0.27–0.83]). CBT had the highest score (p score = 0.8727) across the various psychological interventions. Neither global nor local inconsistencies were significant. There was no clear evidence of violations of the transitivity assumption when comparing characteristics of studies across interventions. Publication bias was not suspected for the primary outcome. Conclusions: CBT may be regarded as a reasonable first-line psychological intervention to prevent re-attempts among people with previous suicide attempts. We observed a moderate quality of evidence supporting an 87% probability of CBT being the best treatment available for preventing suicide re-attempts.
Abstract 4553: How do shiitake and reishi mushrooms work on lung cancer?: A high throughput screening of 3D cell culture
Authors: Mihi Yang, Hee-Kyung Jang, Huiwon Kang
Journal: Cancer Research (2023)

Abstract Shiitake (Lentinula edodes) and reishi mushrooms (Ganoderma sichuanense) have been noticed for desirable chemoprevention, such as improving immunity, overcoming anticancer drug resistance, etc. Particularly, beta-glucans have been mostly mentioned as the active component of the mushrooms. However, the right preparation and effective usage of the mushrooms for cancers are unclear, yet. Thus, we screened various extractions of the two mushrooms and combinations of the extracts, using a high throughput screening of 3D cell culture system on 384-pillar plates with various cancer cells and Cell Titer-Glo 3D cell viability assay kit (Promega). We also quantified the beta-glucans in all extractions with the Megazyme Mushroom and Yeast Beta-Glucan kit (K-YBGL) by excluding the alpha-glucans content from the total-glucans. As results, most of the extracts showed cytotoxicity on the lung cancer cells, A549 cells, rather than on the other cells, such as HepG2 (N=9 for each treatment). The extracts of reishi mushroom in 60% of methanol (dose range, 0.21-2.3 mg/ml) showed the strongest cytotoxicity on the lung cells, IC50=0.90 +/- 0.01 mg/ml, among the extracts of different methanol contents (10-60%) or different temperatures (50-90 °C) of hot water. However, the 60 % of methanol reishi extracts included relatively low levels of beta-glucans, compared to other extracts (18.57 +/- 0.31 vs. 22.42 +/- 5.56 % w/w). In addition, the levels of beta-glucans in all of reishi mushroom extracts were lower than those in all of the shiitake extracts (17.70 +/- 1.89 % vs. 27.05 +/- 4.21 % w/w: p&amp;lt;0.01). Moreover, there was no association between the levels of beta-glucans and IC50 in A549 cells. Interestingly, the combination (1:1) of the above 60% of methanol extracts of reishi mushroom and the 30% methanol extracts of shiitake (dose range, 0.30-3.26 mg/ml) showed synergic effects, i.e., 2-7 fold stronger effects (average of IC50=0.40 mg/ml) than every single treatment (average of IC50=0.90-2.63 mg/ml). Taken together, the reishi mushroom may have other strong chemopreventive materials rather than beta-glucans, while the shiitake may have a potentiation effect, when combined with the reishi mushroom. In conclusion, our 3D cell culture system showed high throughput performance to find the right preparation and effective usage of the two mushrooms and provided useful information for the next clinical studies for lung cancer. Citation Format: Mihi Yang, Hee-Kyung Jang, Huiwon Kang. How do shiitake and reishi mushrooms work on lung cancer?: A high throughput screening of 3D cell culture. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4553.